effect of trikatu, an ayurvedic prescription, on the pharmacokinetic

Indian J Physiol Pharmacol
1999; 43 (1) : 133-136
EFFECT OF TRIKATU, AN AYURVEDIC PRESCRIPTION, ON THE
PHARMACOKINETIC PROFILE OF C,ARBAMAZEPINE IN RABBITS
R. S. KARAN, V. K. BHARGAVA*
Department of Pharmacology,
Postgraduate Institute of Medical
Chandigarh -160 012
AND S. K. GARG
Education
( Received
& Research,
on August
29, 1998)
Abstract:
The effect of single and multiple doses of a herbal preparation
Trikatu
was studied
on the bioavailability
and pharmacokinetics
of
carbamazepine
in rabbits. Rabbits (n=10) were administered
a single dose
of carbamazepine
(80mg/kg; p.o.) and after a washout period of 7 days in
combination
with a single dose of Trikatu (500mg/kg; p.o.). In the other
study, six rabbits were administered
a single dose of carbamazepine
(80mg/
kg; p.o.) before and after multiple doses of Trikatu (500mg/kg X 7d; p.o.),
The blood samples were collected at 0, 1, 2, 4, 6, 9, 12 and 24 hours after
drug administration
and assayed for carbamazepine.
In the animals treated
with single dose of Trikatu,
there was a significant
decrease in Tm•• of
carbamazepine
(P<0.05). Multiple doses of Trikatu also shortened the Tm••
of carbamazepine
although not to statistically
significant level. Our results
suggest that the steeper rise and fall in the plasma levels of carbamazepine
brought about by Trikatu, do not constitute
significant
advantage.
Key words:
trikatu
carbamazepine
INTRODUCTION
'I'r ik at u" a commonly
used herbal
preparation in Ayurvedic medicine, consists
of three crude drugs namely dried fruits of
black pepper (piper nigrum Linn.), dried
fruits of long pepper (piper longum Linn.)
and dried rhizomes of ginger (Zingiber
officinalis Rose.) in the ratio of [1:1:1; w/w]
(1.). The active principle of piper species is
an alkaloid
piperine
or 1-peperoyl
piperidine. Several studies have reported
enhancement of blood levels of drugs like
vasicine, sparteine, phenytoin, propranolol,
theophylline,
sulphadiazine,
tetracycline
*Corresponding
Author
interaction
and rifampicin when coadministered
with
Trikatu or piperine (1-3). The enhanced
plasma levels of drugs has been attributed
to an increase in the rate of absorption of
drugs and to a non specific inhibition of
drug metabolising enzymes by piperine (2,3).
It has been shown to inhibit arylhydro
carbon hydroxylation,
ethylmorphine-Ndemethylation,
7-ethoxycoumarin-odeethylation and 3-hydroxybenzo(a) pyrene
glucuronidation (4-5). Carbamazepine is a
first line drug for the management of partial
and tonic-clonic seizures. Because of limited
aqueous
solubility,
carbamazepine
is
absorbed slowly and erratically after oral
134 Karan
et
al
Indian J Physial Pharmacal 1999; 43(1)
administration
(6). The present study was
planned to see the effect of single and
multiple
doses
of Trikatu
on the
pharmacokinetics
of carbamazepine.
METHODS
The study was carried
out in male
Newzealand white rabbits (1.5-2.5 kg). The
animals were maintained
on a standard
laboratory diet and were housed at ambient
temperature.
All drug administrations
were done at 8 a.m. Trikatu
(500mg)
containing 10mg of pure active principle
piperine
(available
commercially)
and
carbamazepine (Sigma Chemicals, USA) in
pure powder form were used in the study.
Single
dose study:
After overnight
fasting,
ten rabbits
received carbamazepine
(80mg/kg; p.o.)
through an intragastric tube. Blood samples
were collected in heparinized tubes from the
marginal ear vein at 0, 1, 2, 4, 6, 9, 12 and
24 hours after drug administration.
The
rabbits, after a washout period of 7 days
were administered
carbamazepine
(80 mg/
kg; p.o.) alongwith Trikatu (500 mg/kg; p.o.).
Blood samples were drawn at similar time
intervals as with carbamazepine
alone.
Multiple
dose study:
After an overnight fast, six rabbits were
administered carbamazepine (80 mglkg; p.o.)
on day 1. Blood samples were collected at
0, 1, 2, 4, 6, 9, 12 and 24 hours after drug
administration. From day 2 to day 7, rabbits
were treated with Trikatu (500 mg/kg; p.o.)
once daily. On day 8, after an overnight
fast, carbamazepine
(80 mg/kg; p.o.) along
with Trikatu (500 mg/kg; p.o.) was given.
Blood samples were collected at similar time
intervals as on day 1.
Plasma was separated
and stored at
-20°C until assayed for carbamazepine
by
the HPLC method (7). The sensitivity of the
assay method was O.lpg/ml. The intra assay
coefficient of variation at 0.5 ug/ml and 16
ug/ml were 6.83% and 4.96% respectively.
The interassay coefficient of variation at the
same concentration were 8.41% and 6.72%
respectively.
Peak plasma concentration
[CmaJ and time to reach the peak plasma
concentration
[TmaJ were calculated from
the actual plasma data. Rate constant for
elimination
i.e. kel was calculated
by
regression analysis of the monoexponential
declining
line of the log plasma
drug
concentration
versus time graph, while
elimination half life (tl/2e!) was obtained
from the formula t1l2el = 0.6931kel (8). Area
under the plasma drug concentration versus
time curve (AUCO_t) was calculated by the
trapezoidal rule. Extension of the AUC data
to infinity (AUCt_a>was done by dividing
the last observed concentration of drug in
plasma by the elimination
rate constant
(kel ). AUCo_u was the sum of AUCO_t and
AUCt_u' The data was statistically
analysed
by employing the students paired "t" test.
RESULTS
Fig. 1 compares the plasma concentration (mean ± s.e.rn.) of carbamazepine
at
different time intervals, when given alone
or with single dose of Trikatu.
In the
absorption
phase, Trikatu
significantly
enhanced (P<0.05) the plasma concentration
of carbamazepine at 1, 2 and 4 hours after
drug administration.
However no significant
Indian J Physiol Pharmacol
Trikatu-Carbamazepine
1999; 43(1)
Interaction
135
"r-------------------.---, -CBZ
-CBZ+Trikatu
,.
-CBZ
-CBZ+Trikatu
.L--~~=========~
.L,-,--,-,--,--,-,--,-,--,--,,-,-,~,,-,~,~,,~,,~~~,,~,,~,,~~~,~,~,,~,~.~~ o
1
2
)
••
50
,
7
•
•
~
11
12
13
104 15
"
11
HI 11
20
21
U
23
24
""""I
Tlme(h)
Fig. 1: Mean plasma concentration
of carbamazepine
(CBZ, 80 mg/kg, p.o) and carbamazepine
+
Trikatu (500 mg/kg, p.o.) in rabbits (n=10;* =
P<0.05).
Fig. 2: Mean
(CBZ,
doses
(n=6;*
TABLE I : Carbamazepine
kinetics before
single oral dose of Trikatu.
pharmacokinetic parameters (mean ± s.e.rn.)
of carbamazepine before and after multiple
doses of Trikatu. No significant difference
was observed in any of the pharmacokinetic
parameters calculated.
Pharmacokinetic
parameters
Carbamaeepine
and after
Carbamazepine
+ Trikatu
Cmu (ug/ml)
9.38±0.78
T mu (h)
6.00 ±0.58
3.00± 0.42*
Kel (h-1)
0.22 ±0.04
0.22± 0.03
t1l2 el (h)
3.95 ±0.54
3.75± 0.52
92.21 ± 10.45
84.84± 10.42
AUCo-a (ug/rn l.h)
Values represent
plasma concentration
of carbamazepine
80 mg/kg, p.o) before and after multiple
of Trikatu (500 mg/kg, p.o.) in rabbits
= P<0.05).
10.46± 0.38
mean ± SEM (n=10; *P<0.05)
difference was observed in the elimination
phase. Table 1 compares pharmacokinetic
parameters
(mean ± s.e.m.) of carbamazepine before and after single oral dose of
Trikatu. T max in the Trikatu + carbamazepine
group was significantly
lower (P<O.05),
while other pharmacokinetic
parameters
were unaltered.
Figure 2 compares the
plasma concentrations
(mean ± s.e.m.) of
carbamazepine at different time intervals
before and after multiple doses of Trikatu.
In the absorption phase, the mean plasma
concentrations
of carbamazepine
after
Trikatu treatment were significantly higher
at 1 and 4 hours. Table II compares various
TABLE II : Carbamazepine
kinetics before and after
multiple oral doses of Trikatu.
Pharmacokinetic
parameters
Carbamazepine
Carbomazepine
+ Trikatu
Cm •• (ug/rnl)
9.67 ±0.69
10.61± 0.73
T,.ox (h)
4.00±0.73
3.67± 0.61
Kel (h-
0.22 ± 0.03
0.27± 0.03
tl/2 el (h)
3.54 ± 0.58
2.83± 0.37
1)
ALCo-u (ug/ml.h)
Values represent
78.78±7.61
73.77± 6.25
mean ± SEM (n=6)
DISCUSSION
In the present study, coadministration
of single dose of Trikatu
significantly
enhanced
the rate
of absorption
of
carbamazepine.
This
is evident
by,
significantly
high plasma levels in the
absorption phase and a shorter T max in the
Trikatu
group. Similar pharmacokinetic
136 Karan
et
Indian J Physiol Pharmacol
al
changes have been reported for drugs like
phenytoin, propranolol
and theophylline,
when given along with piperine. However
the increase
in the rate of absorption
brought about by piperine has not been
explained so far (2, 3). We believe it could
be. because of increased splanchnic blood
flow and rate of transport
of drugs across
the gastrointestinal
mucous brought about
by Trikatu (9). The other important actions
of Trikatu
on the gastrointestinal
tract
include its ability to increase the gastric
pH and delay the gastric emptying (9).
However
carbamazepine
is a highly
lipophilic, neutral compound and does not
ionize in an aqueous environment (10). Thus
the latter two effects of Trikatu on the
gastrointestinal
tract probably
did not
contribute to the enhanced absorption of
carbamazepine.
The
metabolism
of
carbamazepine follows first order kinetics,
which explains the steep fall in plasma
carbamazepine levels during the elimination
phase in the Trikatu treated group.
1999; 43(1)
The shortening of the T max by multiple
doses of Trikatu
was not statistically
significant.
This could be attributed
to a
smaller sample size (n=6) as compared to
the single dose study (n= 10).
The results further show that single dose
of Trikatu did not significantly
alter the
AUCo_a and tl/2 el of carbamazepine.
These
findings do not correspond with the reported
bioavailability enhancing action of Trikatu.
One possible
inference
is that
the
cytochrome P-450 isoenzymes involved in
carbamazepine metabolism may have a low
or no affinity for piperine. It is also possible
that the isoenzymes
responsible
for the
metabolism of carbamazepine in rabbits may
have different substrate specificities (11).
To conclude, the steeper rise and fall in
the plasma levels of carbamazepine
along
with no change in the AUCo_a and tl/2 el
brought about by Trikatu co-administration,
has no significant advantage.
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